rs553039153

Positions:

• chr19-1226658-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000455.5(STK11):​c.*11C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000265 in 1,510,862 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000026 (0 hom.)
• Consequence: STK11 NM_000455.5 3_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 1.17

Genes affected

STK11 (HGNC:11389): (serine/threonine kinase 11) The protein encoded by this gene is a serine/threonine kinase that regulates cell polarity and energy metabolism and functions as a tumor suppressor. Mutations in this gene have been associated with the autosomal dominant Peutz-Jeghers syndrome, as well as with skin, pancreatic, and testicular cancers. [provided by RefSeq, May 2022]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 19-1226658-C-T is Benign according to our data. Variant chr19-1226658-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 378681.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0000328 (5/152350) while in subpopulation SAS AF= 0.000829 (4/4828). AF 95% confidence interval is 0.000283. There are 0 homozygotes in gnomad4. There are 4 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
STK11	NM_000455.5	c.*11C>T		3_prime_UTR_variant	9/10	ENST00000326873.12	NP_000446.1
STK11	NR_176325.1	n.2580C>T		non_coding_transcript_exon_variant	10/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
STK11	ENST00000326873.12	c.*11C>T		3_prime_UTR_variant	9/10	1	NM_000455.5	ENSP00000324856	P1

Frequencies

GnomAD3 genomes AF: 0.0000328 AC: 5 AN: 152232 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000364 AC: 4 AN: 109824 Hom.: 0 AF XY: 0.0000493 AC XY: 3 AN XY: 60884

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000171

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000303

GnomAD4 exome AF: 0.0000258 AC: 35 AN: 1358512 Hom.: 0 Cov.: 31 AF XY: 0.0000284 AC XY: 19 AN XY: 667896

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000412

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000188

Gnomad4 OTH exome AF: 0.0000356

GnomAD4 genome AF: 0.0000328 AC: 5 AN: 152350 Hom.: 0 Cov.: 33 AF XY: 0.0000537 AC XY: 4 AN XY: 74488

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000829

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Dec 28, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 30, 2015	The c.*11C>T alteration is located in the 3' untranslated region (3'UTR) of the STK11 gene. This alteration consists of a deletion of 1 nucleotides after the last coding exon of the STK11 gene. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 23, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Likely benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Jul 31, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	15
DANN	Benign	0.92

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs553039153; hg19: chr19-1226657;